PROJECT SUMMARY The goals of this project are to improve our understanding of the effects of noninvasive neuromodulation on frontostriatal circuitry in OCD, and to work towards individualized device-based treatment. P4 proposes a series of related, small-scale mechanistic studies which are not intended as treatment trials. Our underlying rationale springs from longstanding research suggesting that cingulotomy is effective in intractable OCD. P4, working in close collaboration with Projects 1, 2 and 3, will first delineate specific brain areas within the dorsal anterior cingulate cortex (dACC), and presupplementary motor area (pSMA), that serve as critical connection nodes mediating neural network abnormalities in OCD. Next, P4 will identify which of three methods of noninvasive stimulation, targeting the same region; will most effectively modulate the network away from abnormalities seen in symptomatic individuals with OCD. We will use these methods to affect activity locally in the dACC and its functional connections. In each case, we will administer open-label stimulation to 20 OCD patients on consecutive weekdays for 6 weeks. MRI will be obtained before and after 6 weeks of stimulation. fMRI-measured activation of dACC during the MSIT task will serve as a biomarker of local dACC responsivity, rs-fMRI will be used to measure functional connectivity of dACC to the network. YBOCS OCD severity will be the primary clinical endpoint in analysis of how local dACC activation and connectivity are associated with symptom change. The simulation methods are: 1) tDCS over dACC-pSMA, representing neuromodulation below threshold for action potential generation. Our pilot work with tDCS in healthy participants suggests that the method might alter a behavioral endpoint (physical distress tolerance) plausibly linked to dACC function. 2) Deep TMS to target dACC directly, using the ?HAC? coil. Our colleagues have recent promising pilot data suggesting that high-frequency deep TMS to dACC, pSMA and other regions of overlying cortex produces therapeutic effects in OCD, associated with normalization of a physiological marker of dACC function, also abnormal in OCD. 3) Focal TMS to pSMA bilaterally. Focal rTMS, delivered chronically to the pSMA appears to show a therapeutic signal in OCD. The pSMA target was based on our group's previous work with TMS in OCD. This will lay the groundwork for application of these noninvasive neuromodulation methods to the large population of OCD sufferers experiencing inadequate improvement after conventional treatments